Understanding energy balance and body weight regulation requires an understanding of the behavioral and neural evaluation of the oral and post-oral sensory signals involved in the control of food intake within a meal, as well as signals related to the availability of stored fuels. Obesity represents an important dysfunctional state of energy balance, and is frequently accompanied by hyperphagia that is manifested by increased meal size. Two mouse models of obesity, the ob/ob mouse lacking leptin, and the db/db mouse, lacking functional leptin receptors (LEPR-B), are also hyperphagic, and exhibit increased meal size without altered meal frequency relative to wild type lean controls. In the proposed studies, we outline behavioral and immunocytochemical studies designed to elucidate the role of leptin signaling in determining the oral and post-oral sensory influences on ingestion in obesity. These experiments will: 1) characterize the ability of oral and upper gastrointestinal (GI) food stimuli to affect food intake within a meal, 2) assess the degree to which genetic leptin signaling deficiency interferes with the feedback potency of oral and upper GI signals in the control of meal size, and 3) characterize the patterns of central nervous system activation excited by oral and GI stimuli that affect meal size in mice with alterations in leptin signaling. We will focus on the C57B6J mouse as the background strain for these studies because: 1) it is has a well-described tendency toward dietary obesity and, 2) it is the background strain for ob/ob and db/db mice. We will evaluate: 1) the ability of leptin to modify the feedback potency of oral and GI food stimuli in ob/ob mice, 2) the ability of transgenic neuron-specific replacement of LEPR-B to restore normal processing of oral and GI food stimuli in db/db mice, and 3) the effect of central vs. peripheral inducible LEPR-B deficiency on eating in mice. To identify central neuronal regions important in leptin's ability to modulate the processing of food stimuli, we will also evaluate the central nervous system patterns of c-Fos expression in these strains in response to selective oral and/or GI food stimuli. This systematic assessment of meal-related stimuli, their central neural representation, and their integration with energy balance peptide signals will significantly advance our understanding of neuro-humoral interactions in the metabolic control of food intake.